The long term objective of this project is to understand how regional pulmonary blood flow (rPBF) is regulated during acute lung injury and how it can be manipulated to improve pulmonary gas exchange. The focus of the proposal will be to determine the structural basis for and natural history of changes in rPBF during experimental high permeability pulmonary edema. We will also examine how changes in rPBF relate to regional changes in extravascular water accumulation and increased pulmonary vascular permeability in the injured lung, as assessed with positron emission tomography (PET). The specific aims of these studies therefore will be: 1) to validate PET as a probe for specifically identifying variably injured lung, 2) to define the extent of regional heterogeneity of such injury, in its various phases of development and resolution, and 3) to study whether manipulating rPBF can affect extravascular lung water accumulation during experimental high permeability pulmonary edema. The strategy of this project is to use PET as a probe to identify areas of acutely injured lung with altered physiology, then to define these same areas of interest in postmortem lung, and finally to characterize and quantify structural derangements in this tissue using histologic, electron microscopic, and morphometric techniques. The relevance of the findings from these structure-function studies will be evaluated by examining what effect mechanical or pharmacological manipulation of rPBF may have on lung water accumulation and pulmonary gas exchange. In the future, parallel studies in humans may be possible to directly evaluate the relevance of these findings in illnesses such as the adult respiratory distress syndrome. Results from this project may ultimately suggest specific therapeutic approaches to control rPBF in acutely injured lung, thereby affecting lung edema formation and pulmonary gas exchange.